FROUNT protein is a cytoplasmic protein that binds to the intracellular C-terminal regions of chemokine receptors CCR2 and CCR5, and positively controls migration signals of macrophages and the like (Patent Document 1, Non-patent Documents 1 and 2). This protein is a novel molecule discovered by the group of the present inventors.
Both CCR2 and CCR5 are known to be involved in cancers and inflammatory diseases, and development of inhibitors for CCR2 and CCR5 has been attempted worldwide aiming at discovery of novel therapeutic agents for these diseases. However, none of these attempts has been successful. The targets of the existing approaches have been the binding between a chemokine CCL2 and a receptor CCR2, the binding between chemokines CCL3 to 5 and a receptor CCR5, and the signal transduction system by PI3K and the like functioning downstream of the receptors. Inhibition of binding of FROUNT protein to the chemokine receptors CCR2 and CCR5 has been expected as a novel drug discovery target (Non-patent Documents 3 and 4).
The present inventors have reported an inhibitor comprising as an effective component a compound represented by the following formula or a salt thereof, as an inhibitor that inhibits interaction between CCR2 or CCR5 and FROUNT protein (Patent Document 1).
(wherein x1 and x2 are the same or different halogens, and R is a lower alkyl.)
Disulfiram has an aldehyde dehydrogenase-inhibiting activity, and inhibits ethanol metabolism in the liver to cause accumulation of acetaldehyde, which is responsible for sickness caused by drinking, in the body. Thus, after taking of disulfiram, symptoms of sickness caused by drinking occur even with a small amount of alcohol. By utilization of this action, disulfiram is used as an anti-alcoholism drug for treatment of chronic alcoholism.
Besides the above-described action, disulfiram is reported to have an action to inhibit the proliferation of cancer cells by induction of their apoptosis (for example, Non-patent Documents 5 to 7). Disulfiram is also reported to have an action to kill hepatic cancer stem cells (Patent Document 2). All these reports are reports on actions for killing cancer cells or cancer stem cells per se. Because of such direct actions on cancer cells, clinical trials targeting cancer are being partially carried out (Non-patent Document 8). However, actions of disulfiram on microenvironment-constituting cells such as immune cells, fibroblasts, vascular endothelial cells and the like present in the vicinity of cancer cells have not been known at all. Actions of disulfiram on inflammatory microenvironments in diseases in which inflammation is involved have not also been known at all.